Project 4: Preventing anti-NMDAR Ab neurotoxicity: Rational therapies for NPSLE (Diamond PI) Compelling data demonstrate that antibodies cross-reactive with DMA and NMDA receptors (NMDARs) can mediate manifestations of neuropsychiatric lupus (NPSLE) in mice. These antibodies can be found in serum, cerebrospinal fluid and brain of lupus patients. We will test the efficacy of the D pentapeptide or candidate modified peptides in models of NPSLE simulating antibody penetration of the blood-brain barrier and antibody production locally within the brain and will determine whether the same peptide(s) can protect fetal brain against potentially neurotoxic antibody when it is present in the maternal circulation. Second, we will inhibit inflammatory mediators of the innate immune response that increase permeability of the blood-brain barrier to see if these agents can prevent LPS or epinephrine-mediated neuroexposure. These studies, in conjunction with other projects in this Program, will hopefully lead to a clinical trial in NPSLE, and provide a paradigm for the development of other therapeutics in immune-mediated brain disease.